Patients with uncontrolled hypertension subjected to cardiopulmonary bypass have altered coronary vasomotor responses to serotonin.

BACKGROUND: We previously found that cardioplegic arrest and cardiopulmonary bypass are associated with altered coronary arteriolar response to serotonin in patients undergoing cardiac surgery. In this study, we investigate the effects of hypertension on coronary microvascular vasomotor tone in response to serotonin and alterations in serotonin receptor protein expression in the setting of cardioplegic arrest and cardiopulmonary bypass. METHODS: Coronary arterioles were dissected from harvested pre- and post-cardioplegic arrest and cardiopulmonary bypass right atrial tissue samples of patients undergoing cardiac surgery with normotension, well-controlled hypertension, and uncontrolled hypertension. Vasomotor tone was assessed by video-myography, and protein expression was measured with immunoblotting. RESULTS: Pre-cardioplegic arrest and cardiopulmonary bypass, serotonin induced moderate relaxation responses of coronary arterioles in normotension and well-controlled hypertension patients, whereas serotonin caused moderate contractile responses in uncontrolled hypertension patients. Post-cardioplegic arrest and cardiopulmonary bypass, serotonin caused contractile responses of coronary arterioles in all 3 groups. The post-cardioplegic arrest and cardiopulmonary bypass contractile response to serotonin was significantly higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups (P < .05). Pre-cardioplegic arrest and cardiopulmonary bypass, expression of the serotonin 1A receptor was significantly lower in the uncontrolled hypertension group compared with the well-controlled hypertension and normotension groups (P = .01 and P < .001). Serotonin 1B receptor expression was higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups post-cardioplegic arrest and cardiopulmonary bypass (P = .03 and P = .046). CONCLUSION: Uncontrolled hypertension is associated with an increased coronary contractile response of coronary microvessels to serotonin and altered serotonin receptor protein expression after cardioplegic arrest and cardiopulmonary bypass. These findings may contribute to a worse postoperative coronary spasm and worsened recovery of coronary perfusion in patients with uncontrolled hypertension after cardioplegic arrest and cardiopulmonary bypass and cardiac surgery.

DPP-4 inhibitor sitagliptin treatment results in altered myocardial metabolic proteome and oxidative phosphorylation in a swine model of chronic myocardial ischemia.

Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.

Sodium-glucose co-transporter 2 inhibitor canagliflozin modulates myocardial metabolism and inflammation in a swine model for chronic myocardial ischemia.

BACKGROUND: Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia. METHODS: Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection. RESULTS: Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment. CONCLUSION: The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways.

Increased Coronary Contraction to Thromboxane A2 in Cardiac Surgery Patients With Poorly Controlled Hypertension.

INTRODUCTION: Cardioplegia and cardiopulmonary bypass (CP/CPB) alters coronary arteriolar response to thromboxane A2 (TXA2) in patients undergoing cardiac surgery. Comorbidities, including hypertension (HTN), can further alter coronary vasomotor tone. This study investigates the effects of HTN on coronary arteriolar response to TXA2 pre and post-CP/CPB and cardiac surgery. MATERIALS AND METHODS: Coronary arterioles pre and post-CP/CPB were dissected from atrial tissue samples in patients with no HTN (NH, n = 9), well-controlled HTN (WC, n = 12), or uncontrolled HTN (UC, n = 12). In-vitro coronary microvascular reactivity was examined in the presence of TXA2 analog U46619 (10-9-10-4M). Protein expression of TXA2 receptor in the harvested right atrial tissue samples were measured by immunoblotting. RESULTS: TXA2 analog U46619 induced dose-dependent contractile responses of coronary arterioles in all groups. Pre-CPB contractile responses to U46619 were significantly increased in microvessels in the UC group compared to the NH group (P < 0.05). The pre-CP/CPB contractile responses of coronary arterioles were significantly diminished post-CP/CPB among the three groups (P < 0.05), but there remained an increased contractile response in the microvessels of the UC group compared to the WC and NH groups (P < 0.05). There were no significant differences in U46619-induced vasomotor tone between patients in the NH and WC groups (P > 0.05). There were no differences in expression of TXA2R among groups. CONCLUSIONS: Poorly controlled HTN is associated with increased contractile response of coronary arterioles to TXA2. This alteration may contribute to worsened recovery of coronary microvascular function in patients with poorly controlled HTN after CP/CPB and cardiac surgery.

Quantification of spinal bone marrow fat fraction using three-material decomposition technique on dual-energy CT: A phantom study.

BACKGROUND: Two-material decomposition is insufficient to quantify the fat fraction of spinal bone marrow, which is comprised of a mixture of bone minerals, water, and yellow marrow (fat). PURPOSE: To develop an accurate three-material decomposition-based bone marrow fat fraction ( F F 3 M D $F{F_{3MD}}$ ) quantification technique for dual-energy CT. METHODS: Bone marrow edema phantoms containing trabecular bone minerals, water, and fat were constructed using fat fractions and bone mineral density values matching those expected in healthy and edematous bone, and scanned on a commercial dual-energy CT. Fat quantified by F F 3 M D $F{F_{3MD}}$ were compared to MRI-based fat fraction ( F F M R I $F{F_{MRI}}$ ) and conventional two-material-decomposition-based fat fraction ( F F 2 M D $F{F_{2MD}}$ ) to evaluate its accuracy and dependency on various bone mineral densities. RESULTS: F F 3 M D $F{F_{3MD}}$ demonstrated an excellent correlation with F F M R I $F{F_{MRI}}\;$ (r = 0.97, R2  = 0.96) in the phantom, significantly more accurate than FF2MD when confounding bone minerals are present (50 mg/cm3 : r = 1.02, R2  = 0.95 vs. r = 0.65, R2  = 0.79 (p < 0.01); 100 mg/cm3 : r = 0.81, R2  = 0.47 vs. r = 0.21, R2  = 0.21 (p < 0.05)). CONCLUSIONS: F F 3 M D $F{F_{3MD}}$ accurately quantified bone marrow fat fraction, when compared with F F M R I $F{F_{MRI}}$ , in the specially constructed bone marrow phantom.

Fat Fraction Measurements Using a Three-Material Decomposition Dual-Energy CT Technique Accounting for Bone Minerals: Evaluation in a Bone Marrow Phantom Using MRI as Reference.

Conventional two-material dual-energy CT (DECT) decomposition is insufficient to model bone marrow, which contains three materials: bone minerals, red marrow (water), and yellow marrow (fat). We explore an image-domain three-material decomposition DECT technique accounting for bone minerals in a bone-water-fat phantom. Three-material decomposition fat fraction (FF3MD) exhibited stronger correlation than two-material decomposition fat fraction (FF2MD) with MRI-based fat fraction (r = 0.95 vs r = 0.69). With increasing bone minerals, correlation of FF3MD remained stable (r = 0.81-1.02), whereas correlation of FF2MD decreased (r = 0.21-0.65).

Quantification of Degree of Liver Fibrosis Using Fibrosis Area Fraction Based on Statistical Chi-Square Analysis of Heterogeneity of Liver Tissue Texture on Routine Ultrasound Images.

RATIONALE AND OBJECTIVES: We present a novel method to quantify the degree of liver fibrosis using fibrosis area fraction based on statistical chi-square analysis of heterogeneity of echo texture within liver on routine ultrasound images. We demonstrate, in a clinical study, that fibrosis area fraction derived this way has the potential to become a noninvasive, quantitative radiometric discriminator of normal or low-grade liver fibrosis (Ishak fibrosis score range = F0-3) and advanced liver fibrosis or cirrhosis (Ishak fibrosis score range = F4-6) on routine ultrasound images. MATERIALS AND METHODS: This retrospective patient study was institutional review board approved. Ultrasound images of 100 patients (61 males, 39 females; 18-81 years) who underwent nontargeted ultrasound-guided biopsy were randomly divided into two groups: a training group consisted of 31 cases, and a validation group that contained the rest cases. An investigator manually selected a primary region of interest (ROI; approximately 4-6 cm2) in the liver tissue while avoiding nonhepatic parenchyma. The primary ROI contained a large number of secondary ROIs (25 × 25 pixels) to maintain the precision of statistical analysis. Sample variance σ2 of image gradient (a texture feature related to the amount of edge structures) was calculated in secondary ROIs in a roster scan fashion. A theoretical derivation was presented to estimate population variance [Formula: see text] of image gradient across the primary ROI from mean gradient µ of secondary ROIs. The χ2 (χ2 = σ2/ [Formula: see text] ) was computed at each secondary ROI, forming a χ2 map of liver tissue heterogeneity. A cut-off value was optimized from datasets in the training group by comparing to the fibrosis grades determined by biopsy. This cut-off value was then applied to the datasets in the validation group to convert the χ2 maps into binary images, from which fibrosis area fractions (fraction of fibrosis area to the total area of the primary ROI) were calculated and entered in a statistical analysis. RESULTS: In the training group, the optimal setting was found to be [Formula: see text] = 6.0, which resulted a maximum discrimination of F0-3 vs F4-6: p < 0.0001, area under curve = 0.985, sensitivity = 93.7%, specificity = 93.3%. When this setting was applied to the datasets in the validation group, a distinct separation was seen between the two classes (p < 0.0001). F0-3 class had an average fibrosis area fraction of 4.7% (1.7%-11.4%), whereas the F4-6 class had an average fibrosis area fraction of 17.3% (9.8%-29.6%). A strong correlation was demonstrated between the fibrosis area fraction and histological fibrosis grade determined by biopsy (area under curve = 0.89, sensitivity = 87.9%, specificity = 90.3%). CONCLUSION: The presented method is a promising noninvasive tool for distinguishing normal or low-grade liver fibrosis (F0-3) and advanced liver fibrosis or cirrhosis (F4-6) from routine ultrasound images. These findings support the further development of texture heterogeneity analysis, particularly fibrosis area fraction, as a quantitative biomarker for distinguishing various liver fibrosis grades.